This research application will exploit a newly discovered Hantavirus pulmonary syndrome (HPS) rodent model to discover and test post-exposure prophylactics and therapeutics for treatment of HPS. A brief description of the model is as follows: adult Syrian hamsters injected with Andes virus (ANDV) (a hantavirus that causes the majority of HPS cases in South America) develop a fatal disease that is strikingly similar to the disease in humans (e.g. approximately 2 week incubation period, rapid onset, pulmonary edema, plural effusions, highly lethal). The pathogenesis of HPS in neither humans nor hamsters is understood. Moreover, there are no vaccines or specific drugs to prevent or treat HPS. Broadly speaking, we wish to advance the development of countermeasures to prevent and treat disease caused by ANDV and other highly pathogenic hantaviruses. Here, we will fully characterize the ANDV/hamster HPS model (Aim 1). We will identify viral virulence factors by generating reassortant Hantaviruses and isolating variant viruses (Aim 2). Concurrently, we will test candidate small molecule drugs for a capacity to prevent HPS in the hamster model (Aim 3). Further, we will evaluate the effectiveness of ribavirin in the ANDV/hamster model and examine its potential to cause error catastrophe. When completed, this research will result in a fully characterized HPS rodent model, an understanding of HPS pathogenesis, and insight into the effectiveness of antiviral based counter measures to treat HPS.